GVHD is a sometimes fatal, often debilitating complication that arises in patients who have received allogenic bone marrow transplants. Marrow transplants become necessary in the treatment of certain diseases, such as leukemia, aplastic anemia or certain genetic disorders, in which the patient's own marrow is severly flawed and where total body irradiation or chemotherapy destroy the patient's hematopoietic system. Absent reconstitution of the hematopoietic system, the patient will be severely immunodepressed and susceptible to infection. Hence GVHD is frequently encountered in bone marrow transplantation and presents a major obstacle to the successful treatment of the above disorders.
Working with the H2 histocompatability system of mice, Korngold and Sprent, Immunological Rev., 71:5 (1983), have reviewed the suspected etiology and pathology of GVHD. Briefly, in its acute form, GVHD is an extraordinarily morbid and often fatal disorder which is primarily, if not exclusively, mediated by T lymphocytes. It typically results from the incomplete immunologic matching of donor with recipient Human Leukocyte antigens (HLA). There are four major HLA antigens: the Class I HLA-A, HLA-B and HLA-C antigens; and the Class II HLA-D region antigens. These antigens form the major histocompatability complex (MHC), and are expressed in virtually all cells, including nucleated cells in the bone marrow. MHC antigens are cell surface glycoproteins expressed on the lipid membrane. These HLA antigens can trigger the immune system (principally T cells) to respond to foreign antigens. For a more detailed description of the HLA system, see P. Weisz-Carrington, Principles of Clinical Immunohematology, p. 218, YearBook Medical Publishers, Inc. (1986).
Even in those cases where the most complete HLA matching is correctly done, GVHD frequently results. It has been suggested that GVHD results, in those instance, from alloaggression due to minor histocompatability antigen differences for which many authors have suggested the depletion of donor T cells as a means to avoid GVHD.
Korngold and Sprent were the first to suggest that not all T cells, however, are necessarily involved in inducing GVHD. T cells (CD3.sup.+) have two major subset populations: T helper/inducer cells (CD4.sup.+) and T cytotoxic/suppressor cells (CD8.sup.+). These authors suggested in 1983, on the basis of experiments with a single MHC compatible pair of mouse strains, that the CD8.sup.+ subset appears to be involved in GVHD. Later, however, B. Hamilton, J. Immunol., 139:2511 (1987) and Korngold and Sprent (1987) reported on experiments in multiple strains of mice. They showed that in some strains merely by depleting T cytotoxic/suppressor cells (Lyt2.sup.+ in mice) did not abolish GVHD in all mouse strains, but that depletion of L3T4.sup.+ cells also was required for some strain combinations.